About 90% of the human HIV infections are caused by a HIV-1 virus. Human immunodeficiency virus type 1 (HIV-1) is characterized by a striking genetic variability caused by accumulation of mutations, arising during viral replication, and also caused by the recombination events. Long term failure of chemotherapeutic methods of HIV treatment are notably explained by the high mutagenic activity of HIV-1 viral strains. It was shown earlier that resistant viral variants quickly have been arisen in patients after different courses of antiretroviral therapy and even after multidrug therapy (HAART). These resistant viruses bear specific alterations in their proteins conformation and structure. Usually such mutations responsible for HIV-1 escape from current treatments are maintained through the successive virus generations and accumulate, as a result of selection under the treatment conditions.
Treatment with anti-HIV-1 medicines does not totally block replication of the virus, which allows a selection and accumulation of pre-existing resistance mutations, as well as of newly occurring mutations, thus bringing new opportunities for the virus to go on spreading. The existing antiretroviral medicines (NRTI, NNRTI, protease inhibitors, fusion inhibitors and mixtures thereof, like HAART) can only slow down the HIV-1 replication for a more or less prolonged period of time, until the arising and propagation of resistant viral strains. The wide spreading of HIV-1 resistant variants raises serious concerns and requires the availability for further anti-HIV-1 therapeutic tools.
Various anti-HIV therapeutic strategies, other than those making use of chemical anti-retroviral substances, have been considered, which include (i) the use of anti-HIV antibodies, (ii) HIV particles disruption-based vaccines, (iii) HIV peptides-based vaccines and (iv) DNA plasmid or viral vector-based vaccines, each having their specific drawbacks.
As the HIV pandemic continues to infect millions of people each year, the need for an effective vaccine increases. The development of anti-HIV vaccines has been deeply impaired, due to the difficulty in developing an immunogenic product capable of eliciting broadly neutralizing anti-HIV antibodies.
Induction of broadly neutralizing antibodies (bNAb) against primary isolates of human immunodeficiency virus (HIV) remains a major and unmet goal for AIDS vaccine research. Early attempts using envelope-based vaccines have elicited antibodies that are effective only against laboratory-adapted isolates. In these instances, protection has been correlated with high titer bNAb directed to the V3 hypervariable region of gp120. However, neutralizing activities generated are largely isolate-specific and are minimally effective against most primary isolates of HIV-1. The failure of subunit gp120 vaccines to protect against HIV-1 acquisition in Phase III clinical trials underscores the difficulty of the task.
Nevertheless, bNAb can often be found in HIV infected individuals. Responses generated early in infection are usually narrow in specificity, neutralizing the transmitted viruses in the host, but not the contemporaneous ones. Such responses broaden during the course of infection in some long-term survivors who are able to control their infection in the absence of antiviral treatment. However, the nature of the cross-neutralizing antibody response and the mechanisms leading to its genesis are not understood.
Naturally, NAbs against Env are generated within weeks after infection, but this early response is only efficient against a specific viral subtype; however, bNAbs (cross-reactive neutralizing Abs) can develop during the course of HIV. Recently several major studies have shown that approximately 25% of HIV-infected subjects (infected for at least 1 yr) have bNAb response, and 1% of “Elite neutralizers’ with very robust activity against a great majority of clades. Importantly, these results demonstrate the ability of the immune system of infected persons to in vivo generate NAbs against HIV-1, during the course of the disease. They also suggest that broadly reactive Nab activities seem to develop over time and are fostered by chronic antigen exposure, in absence of knowledge about the titer of bNAbs that would be protective.
Persistent viral replication, in low noise, leads to a continuous evolution of Env to evade NAbs. Such antigenic evolution may focus new vaccine strategy on the more conserved region of the Env protein, and suggest that vaccine immunogens could be designed to mimic key highly conserved epitopes.
One of the major obstacles to the design of efficient anti-HIV vaccines has been that the target of bNAbs is the viral envelope protein (Env), which is highly variable, whereas the conserved elements seem to be poorly immunogenic. This means that kinetic and special constraints impede bNAbs from accessing potentially vulnerable sites during receptor binding and fusion processes. Actually few amount of NAbs have been described. For example, the first bNAb identified was b12, which occludes the CD4 binding site on gp120 and prevents CD4 attachment. The gp41 subunit is far more conserved than is gp120 involving conformational rearrangements is common to all stains. Very little bNAb activities are elicited against conserved structural elements of the gp41 that are shielded, difficult to access or transient; those bNAbs, including 2F5 and 4E10, targets the membrane-proximal ectodomain region (MPER) of gp41. However, immunization with these key epitopes did not result in the generation of bNAb activity. This dichotomy between the antigenic and immunologic characteristics is still not understood.
There is still a need in the art for therapeutic tools aimed at preventing or treating an infection caused by an HIV-1 virus.